Cytokines regulate cellular growth and differentiation, along with immune and inflammatory responses. They are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, lupus, IBD, psoriasis, allergy and asthma. Targeting cytokines and cytokine signaling has led to successful new strategies for treating these diseases, underscoring the need to better understand the molecular basis of cytokine action as it relates to the pathogenesis of immune-mediated disease. A critical means by which cytokines exert their effect is activation of receptor-associated Janus kinases, or JAKs, and the activation of a family of transcription factors called STATs; this has been the focus of our work for the last two decades. One important action of cytokines in which STATs play a key role is the differentiation and activation of different subsets of lymphocytes to attain distinct fates, as well as the induction of other cytokines. The control lymphocyte differentiation by transcriptomic and epigenomic regulation has been a longstanding interest of the lab. Our previous work has documented critical functions of STAT5 in CD4+ helper T cells, ranging from suppression of follicular helper T cell function to promotion of regulatory T cells. STAT5 is also known to favor the generation and survival of memory T cells. In this years work, we identified an unexpected role for STAT5 signaling in the death of effector memory T cells in mice and humans. We identified a patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to Stat5 - deficient mice, this patient exhibited increased CD4+ memory cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes. Notably, CD4+ memory cells from the patient were strikingly resistant to cell death by in vitro TCR re-stimulation, a finding that was recapitulated in Stat5b deficient mice. Thus, our work indicates that in addition to other functions in T cells, including growth promoting and anti-apoptotic functions of STAT5, paradoxically, STAT5 is also a relevant factor that promotes cell death in memory T cells in mice and humans. IL-7 is a critical cytokine that regulates homeostatic mechanisms that maintain the overall size of the T cell pool and much of its activity can be explained by the actions of STAT5. However, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in enhanced IL-7-dependent STAT1. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Thus, our data suggests that T cells in a lymphopenic state (e.g. HIV infection) upregulate STAT1 protein, switching on an alternate IL-7-dependent program. We propose that this mechanism could be a pathophysiological process that impacts expansion and size of the CD4+ T cell pool. A consequence of HIV infection may be enhanced STAT1 activation and dysregulation of lymphocyte homeostasis via this mechanism. In related collaborative work, we showed that skin commensals such as S. epidermidis elicit IL-17- (Tc17) and interferon gamma- (Tc1) producing CD8 T cells. These T cells respond to N-formyl methionyl peptides, a sequence used for initiation of bacterial translation presented by non-polymorphic MHC molecules. Analysis of their transcriptomes of these cells revealed evidence of tissue repair function beyond typical effector functions. This work shows that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota through the specification of CD8 T cells that promote wound healing. This year we also reported our work showing critical roles of STAT5 alleles in the development and homeostasis of innate lymphoid cells (ILCs). ILCs comprise a diverse collection of lymphocytes that patrol environmental interfaces to defend against infection and protect barrier integrity. We showed that STAT5 is critical for accumulation of all known ILC subsets in mice and documented a hierarchy of STAT5 dependency for the different ILC subsets. We also showed that activation of ILCs is associated with redistribution of STAT5 that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our work established STAT5 as a central node that instructs ILC development, homeostasis, and function. Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. This year we reported the identification of a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs we termed Rroid, which interacts with the Id2 promoter. Mechanistically, we found that Rroid locus controls chromatin accessibility and deposition of STAT5 at the Id2 promoter in response to interleukin (IL)-15. Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. In this years work, we examined that initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features. We found that NCR+ ILC3 exhibited high basal expression of the STAT4 due to expression of T-BET. As a result, IL-23, by accessing STAT4, induced expression of IL-22, followed by a production of IFN gamma.